ANGPTL3 in the Peripheral Circulation Is Associated with Resistance to Anti-PD1 Therapy in Advanced Gastric Cancer.

[UNLABELLED] Anti-PD1/-PDL1 therapy has attracted great attention in cancer therapy in recent years, but a serious problem remains that only a small portion of patients can benefit from it. In this study, we attempted to identify a molecule that is associated with anti-PD1/-PDL1 therapeutic efficacy through proteomic profiling of plasma obtained from patients with advanced gastric cancer (AGC) receiving anti-PD1 nivolumab monotherapy. We collected peripheral blood from 91 patients with AGC before and after nivolumab treatment, and plasma was analyzed by the SomaScan v4.1 and ELISA. Relationships between the levels and patient prognosis were statistically analyzed. To evaluate antitumor effects induced by blocking the identified molecule for which high levels were significantly associated with poor prognosis, in vivo therapeutic experiments using mouse tumor models were conducted. Proteomic data revealed that the levels of 14 molecules both before and after treatment were significantly higher in patients with progressive disease (PD) than those in non-PD patients. Among them, angiopoietin-like 3 (ANGPTL3) levels were notably higher in PD patients than those in non-PD patients, and patients with high levels of ANGPTL3 either before or after treatment showed significantly worse prognosis. In mouse tumor models with increased ANGPTL3, anti-ANGPTL3 therapy significantly reduced tumor growth and synergistically enhanced anti-PD1 therapeutic efficacy. These suggest that high levels of ANGPTL3 in plasma are a significant risk factor associated with unresponsiveness to anti-PD1 treatment and poor prognosis. Targeting ANGPTL3 in the peripheral circulation may be a promising strategy to improve clinical outcomes in anti-PD1/-PDL1 therapy for AGC.

[SIGNIFICANCE] This study provides valuable evidence suggesting the importance of targeting peripheral ANGPTL3 in the anti-PD1/-PDL1 therapy for AGC and will encourage and accelerate the development of a useful biomarker to predict responders/nonresponders to the therapy, leading to improved clinical outcomes in the treatment of gastric cancer.